The present invention concerns 19-nor steroid compounds, substituted in position 11xcex2, their preparation process and intermediates, their application as medicines and the pharmaceutical compositions containing them.
Osteoporosis is a pathology that is characterised by a quantitative and qualitative reduction of the bone tissue, sufficient to lead to vertebral or peripheral fractures, in a spontaneous manner or with minimum traumatism. Although this ailment is of multifactorial origin, it is the menopause that, in women, constitutes the dominating factor of bone loss or osteopenia.
This osteopenia shows itself by rarefaction and modification of the structure of spongy bone which has the consequence of accentuating skeletal fragility and the risk of fracture. The bone loss strongly accentuates after the menopause because of the suppression of ovarian function and reaches 3 to 5% per year to slow down after the age of 65 years.
In a therapeutic objective, postmenopausal hormonal deficiency can be compensated by hormone replacement therapy where oestrogen plays a major role in preserving the bone reserves. But long term oestrogen therapy is sometimes accompanied by undesirable effects on the genital organs (endometrial hyperplasia, mammary tumours), this constitutes a major drawback and limits its application.
It is thus advisable to find other compounds than oestradiol with a dissociated oestrogen activity, namely oestrogen activity at bone level, whilst having little or no endometrial hyperplasia activity, nor the activity of proliferating mammary tumours.
The invention thus has as its object the compounds of general formula (I): 
in which:
R1 represents a hydrogen atom, a (CH2)m-Ar, (CO)-Ar, (CH2)m-Alk or (CO)-Alk radical,
R2 represents a radical derived from a saturated or unsaturated, linear or branched hydrocarbide containing from 1 to 6 carbon atoms
D represents the residue of a pentagonal or hexagonal ring optionally substituted and optionally unsaturated,
X represents a halogen or hydrogen atom, n is equal to 3, 4 or 5, either identical or different R3 and R4 representing a hydrogen atom, a (CH2)m-AR, (CH2)m-Het or (CH2)m-Alk group,
or R3 and R4 together with the nitrogen atom to which they are linked form an aromatic or non aromatic, saturated or unsaturated mono or polyclique heterocycle, with 3 to 15 bonds optionally containing from 1 to 3 additional heteroatoms chosen from amongst non substituted or substituted oxygen, sulphur and nitrogen,
Ar representing a carbocyclic aryl group containing from 6 to 18 atoms of carbon, Het representing a saturated or unsaturated aromatic or non aromatic heterocycle, comprising from 1 to 9 carbon atoms and from 1 to 5 heteroatoms chosen from amongst oxygen nitrogen or sulphur atoms, Alk representing a radical derived from a non aromatic, linear, branched or cyclique, saturated or unsaturated hydrocarbide and comprising from 1 to 12 carbon atoms, the Ar radicals Het or Alk can be substituted or non substituted, m represents 0, 1, 2 or 3, as well as their addition salts with the bases or the acids.
By halogen is meant: iodine, bromine, chlorine or fluorine.
By (CH2)m is meant the following values: single bond in the event that m is equal to 0, CH2, (CH2)2 and (CH2)3.
By the term Ar representing the carbocyclic aryl group containing from 6 to 18 carbon atoms, is meant an aromatic cyclic hydrocarbide derivative such as the phenyl, naphtyl, phenanthrenyl radical or even a condensed bicyclic or tricyclic hydrocarbide derivative comprising a benzene ring like indanyl, indenyl, dihydronaphtyl, tetrahydronaphtyl or fluorenyl. The coupling is made at the benzene ring. It preferably concerns phenyl.
By the term (Het) representing an aromatic or non aromatic, saturated or unsaturated heterocycle, comprising from 1 to 9 carbon atoms and from 1 to 5 heteroatoms chosen from amongst oxygen, nitrogen and sulphur atoms these are notably designated:
Heterocyclic monocyclic radicals, for example thienyl, furyl, pyrannyl, pyrrolyl, imadazoyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazannyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazollinyl, triazolyl, tetrazolyl,
the heterocyclic condensed rings, for example benzofurannyl, benzothienyl, benzimidazoyl, benzothiazolyl, naphto [2,3-b] thienyl, thianthrenyl, isobenzofurannyl, chromenyl, xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phtalazinyl, naphtyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indolinyl, isoindolinyl, imidazopyridyl, imidazopyrimidinyl radicals or even condensed polycyclic systems, made up of monocyclic heterocyclics like those defined above like for example furo[2,3-b]pyrrol or thieno[2,3-b]furan,
or saturated heterocycles such as pyrrolidine, piperidine and morpholine.
By the term (Alk) representing a radical derived from a saturated or unsaturated, branched or cyclic, linear, non aromatic hydrocarbide, are designated, in the case of acyclic hydrocarbides alkyl radicals such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, 2-methyl pentyl, 2,3-dimethyl butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, n-octyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl3-ethylpentyl, nonyl, 2,4-dimethylheptyl or n-decyl, radical alkenyls such as vinyl, propenyl, isopropenyl, allyl, 2-methylallyl, butenyl or isobutenyl, or alkynyl radicals such as ethynyl, propynyl,propargyl, butynyl or isobutynyl, and in the case of cyclic radicals, the cycloalkyl radicals, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Preferably methyl and ethyl radicals are used.
By CO-Alk is preferably meant COCH3 and COEt, by CO-Ar is preferably meant the benzoyl radical, when m is different to zero, (CH2)m-Ar will preferably be the benzyl group.
When R3 and R4 together with the nitrogen atom to which they are linked form a heterocycle, they are notably mono or bicyclic heterocycles optionally containing another heteroatom chosen from amongst oxygen and nitrogen such as the following unsaturated heterocycles: pyrrolyl, imidazolyl, indolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazoyl, furazolinyl, pyrazolinyl, thiazolinyl, or more particularly, the following saturated heterocycles: 
When the different Alk, Ar, Het groups as well as the residue of a pentagonal or hexagonal ring cited earlier are substituted, they could notably be so by the following radicals: halogen, namely fluorine, chlorine, bromine or iodine, alkoxy such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, amino, alkylamino such as methylamino or ethylamino, dialkylamino such as dimethylamino, diethylamino, methylethylamino, each of these dialkylamino radicals being optionally in oxidised form, aminoalkyl such as aminoethyl or aminoethyl, dialkylaminoalkyl such as dimethylamino methyl or ethyl, dialkylaminoalkyloxy such as dimethylamino ethyloxy, optionally acylated hydroxyl, acyl such as acetyl, propionyl, butyryl, benzoyl, free carboxy, esterified like alkoxy carbonyl for example methoxy carbonyl or ethoxy carbonyl, cyano, trifluoromethyl, aryl such as phenyl, aralkyl such as benzyl, alkyl, alkenyl or alkynyl these radicals being themselves optionally substituted by the halogen, alkyl, alkoxy, alkylthio, amino, alkylamino or dialkylamino radicals indicated above.
Of course, the expression xe2x80x9csubstitutedxe2x80x9d indicates that one or several identical or different substitutes, can be present. As an example, when the alkyl group is a methyl radical substituted by one or several halogen atoms, it can notably be CH2Cl, CH2F, CHF2 and CF3.
In the case of (Het), the substitutes can be at the level of NH or of a carbon atom.
Of course the values of R1, R2, R3, and R4, are independent from each other.
The invention naturally extends to the salts of the compounds of formula (I), like for example the salts formed with mineral or organic acids on the amine. It can thus concern chlorohydric, bromhydric, nitric, sulfuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartric, citric, oxalic, glyoxylic, aspartic, alcane sulfonic acids such as methane or ethane, sulfonic, arylsulfonic acids, like the sulfonic and arylcarboxylic benzene or paratoluene acids. When the compounds of formula (I) include an acid function, the invention extends to the optionally substituted salts of alkaline, earthy alkaline or ammonium metals.
The invention more particularly has as its object the compounds of general formula (I) as described above, in which (D) represents the residue of a pentagonal ring of formula: 
in which
R2 retains the same signification as before,
either R5 represents an OH, Oxe2x80x94(CH2)m-Alk, Oxe2x80x94(CO)-Alk, Oxe2x80x94(CH2)m-Ar,Oxe2x80x94(CO)-Ar,Oxe2x80x94(CH2)m-Het, Oxe2x80x94(CO)-Het and R6 represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical containing from 1 to 6 substituted or non substituted carbon atoms, m, Alk, Ar and Het as previously described,
or R5 and R6 together with the carbon atom which carries them form in one of the following rings: 
xe2x80x83in which
z represents axe2x80x94(CH2)1xe2x80x94orxe2x80x94CHxe2x95x90CHxe2x80x94(CH2)1xe2x80x2 group, 1 being an integer between 1 and 4 and 1xe2x80x2being an integer equal to 1 or 2,
either R5 and R6 together form an oxo group, as well as their addition salts with the acids or the bases.
The invention has more particularly as its object the compounds of formula (I) as previously described corresponding to general formula (Ixe2x80x2): 
in which:
X represents a chlorine, bromine or hydrogen atom, nxe2x80x2 is equal to 3,
or identical or different Rxe2x80x23 and Rxe2x80x24 represent an alkyt radical containing from 1 to 6 carbon atoms
or Rxe2x80x23 and Rxe2x80x24 together, with the atom of nitrogen to which they are linked, form a saturated mono or polyclic residue with 3 to 15 bonds optionally containing an additional heteroatom chosen from amongst oxygen, sulphur and nitrogen,
Rxe2x80x25 and Rxe2x80x26 have the same signification as R5 and R6,
as well as their addition salts with the acids and the bases.
The invention has more particularly as its object the compounds of formula (I) as previously described corresponding to general formula (Ixe2x80x2) in which:
either Rxe2x80x25 represents an OH radical and Rxe2x80x26 a hydrogen atom, an alkyl, alkenyl or alkynyl radical containing from 1 to 6 substituted or non substituted carbon atoms,
or Rxe2x80x25 and Rxe2x80x26 together with the carbon atom which carries them form one of the following rings: 
xe2x80x83or Rxe2x80x25 and Rxe2x80x26 together form an oxo group, as well as their addition salts with the acids or the bases.
The invention has more particularly as its object the compounds of formula (I) corresponding to general formula (Ixe2x80x2) as previously described in which:
Xxe2x80x2 represents a chlorine or hydrogen atom,
nxe2x80x2 is equal to 3,
either identical or different Rxe2x80x23 and Rxe2x80x24 represent an alkyl radical containing from 1 to 6 carbon atoms
or Rxe2x80x23 and Rxe2x80x24 together with the nitrogen atom form the following saturated heterocycles: 
xe2x80x83and either Rxe2x80x25 represents an OH radical and Rxe2x80x26 represents a hydrogen atom,
an alkyl, alkenyl or alkynyl radical containing from 1 to 6 carbon atoms, substituted or not,
or Rxe2x80x25 and Rxe2x80x26 together with the carbon atom which carries them form one of the following rings: 
xe2x80x83or Rxe2x80x25 and Rxe2x80x26 together form an oxo group,
as well as their addition salts with the acids or the bases.
The invention has more particularly as its object either the compounds of general formula (I) as previously described in which Xxe2x95x90H, or the compounds of general formula (I) as previously described in which Xxe2x95x90Cl or Br, and more particularly Cl.
The invention has very particularly as its object the compounds of formula (I) as well as their addition salts with the acids whose names are the following:
3-hydroxy-11xcex2-[4-[3-(1-piperidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-17-one,
3-hydroxy-11xcex2-[4-[3-(1-pyrrolidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-17-one,
3-hydroxy-11xcex2-[4-[3-dimethylamino)propyl]phenyl]-estra-1,3,5(10)-trien-17-one,
4-chloro-3-hydroxy-11xcex2-[4-[3-(1-piperidinyl)propyl]phenyl]-estra-1,3,5(10) -trien-17-one
4-chloro-3-hydroxy-11xcex2-[4-[3-(1-pyrrolidinyl)propyl]phenyl]-estra-1,3,5(10) -trien-17-one
4-chloro-3-hydroxy-11xcex2-[4-[3-(diethylamino)propyl]phenyl]-estra-1,3,5(10) -trien-17-one
11xcex2-[4-[3-(1-pyrrolidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-3,17xcex2-diol,
11xcex2-[4-(3-dimethylamino)propyl)phenyl]-estra-1,3,5(10)-trien-3,17xcex2-diol
11xcex2-[4-(3-(1-piperidinyl)propyl)phenyl]-estra-1,3,5(10)-trien-3.1 7xcex2-diol
4-chloro-11xcex2-[4-[3-(1-pyrrolidinyl)propyl]phenyl]-estra-1,3,5(10) -trien-3,17xcex2- diol
4-chloro-11xcex2-[4-[3-(1-piperidinyl)propyl(]phenyl]-estra-1,3,5(10) -trien-3,17xcex2-diol
4-chloro-11xcex2-[4-[3-(diethylamino)propyl]phenyl]-estra-1,3,5(10)-trien-3,17xcex2-diol,
17xcex1-methyl-11xcex2-[4-[3-(1-piperidinyl)propyl]phenyl]-estra-1,3,5(10)-trien -3,17xcex2-diol,
4-chloro-17xcex1-methyl-11xcex2-[4-[3-(1-piperidinyl)propyl]phenyl]-estra-1,3,5(10) -trien-3,17xcex2-[diol
11xcex2-[4-[3-(1-piperidinyl)propyl]phenyl]-17xcex1-(trifluoromethyl)-estra-1,3,5(10) -trien-3,17xcex2-diol]
(17R)11xcex2-[4-(3-dimethylamino)propyl)phenyl]-spiro-(estra-1,3,5(10)-trien -17,2xe2x80x2(5xe2x80x2H)-furan)-3-ol
(17R)4xe2x80x2.5xe2x80x2-dihydro-11xcex2-[4-(3-dimethylamino)propyl)phenyl]-spiro-(estra -1,3,5(10)-trien-17,2xe2x80x2(3xe2x80x2H)-furan)-3-ol.
The invention equally has as its object a preparation process for the compounds of formula (I) as previously described in which a compound of formula (II) is submitted: 
in which
D and R2 are as previously described and K represents a protector group of 3-ceto function, successive to the following reactions:
a) action of a formula (III) compound: 
xe2x80x83in which, M represents a metallic derivative, P represents an alcohol protector group and n is an integer equal to 3, 4 or 5, then optionally deprotection of one or several protected reagent functions, in order to obtain a formula (IIIa) compound: 
xe2x80x83Pxe2x80x2 having the same values as P as well as hydrogen,
b) action, optionally, of a halogenation reagent, in order to obtain a formula (IIIb) compound: 
xe2x80x83Hal representing a halogen atom,
c) after having optionally protected and/or activated the OH function, action of an aromatisation reagent of ring (A) on the formula (IIIa) and (IIIb) compounds, then action of a base to obtain the formula (IV) compound: 
xe2x80x83Pxe2x80x3 having the same values as pxe2x80x2 and able moreover to represent an activating group,
X being as previously described,
d) action of a formula (V) amine: 
xe2x80x83R3 and R4 being as previously defined, this compound optionally being in the form of a salt, in order to obtain certain compounds of formula (I), the compounds of formulas (IIIa), (IIIb), (IV) and (I) being submitted if desired or if necessary, in a suitable order, to one or several of the following reactions:
protection/deprotection of the OH group(s),
alkylation/acylation of the OH group(s),
action of a reduction agent when D represents the residue of a pentagonal ring as previously described and R5 and R6 together form an oxo group,
action of an organometallic or CF3SIMe3 on the compounds of formula (IV) or (I) with D representing the residue of a pentagonal ring as previously described and R5 and R6 together forming an oxo group,
action of a lactonisation agent on the compounds of formula (IV) or (I) with D representing the residue of a pentagonal ring as previously described and R5 and R6 together forming an oxo group,
action of a reduction agent of the double bond, when D represents the residue of a pentagonal ring as previously described and R5 and R6 together with the carbon that carries them, form an Oxe2x80x94(CH2)1xe2x80x2xe2x80x94CHxe2x95x90CHxe2x80x94,
action of a reduction agent, when D represents the residue of a pentagonal ring as previously described, and R6 is an alkenyl or alkynyl radical containing from 2 to 6 carbon atoms,
salification.
The action of a compound of formula (III) on the compound of formula (II) is preferably carried out in the presence of a copper salt such as copper chloride I.
The action of a halogenation reagent such as N-bromosuccinimide or N-chlorosuccinimide on the compounds of formula (IIIa) is notably carried out in the presence of a dipolar aprotic solvent such as dimethylformamide.
The reaction of aromatisation followed by the reaction of saponification (basic action) is carried out according to standard methods such as are described in European patent 0097572. Preferably a compound of acetic anyhydride and acetyl bromide is used as aromatisation agent then a base such as soda in methanol as saponification agent.
By activation of the alcohol is meant the introduction notably of a mesylate, tosylate or triflate which makes it possible to facilitate the nucleophile substitution of the amine of formula (V) on the compounds of formula (IV). The formation of the mesylate, tosylate or triflate from compounds of formula (IIIa) or (IIIb) with Pxe2x80x2 representing hydrogen is carried out in the presence of a base such as triethylamine.
The substitution of alcohol with a halogen atom can equally be envisaged.
The protection and deprotection reactions are standard methods known to a specialist. A quite comprehensive review is found in the following work: Protective groups in organic synthesis T. W. Greene, John Wiley and sons (1981).
The protector group P can represent an alkyl radical containing from 1 to 4 carbon atoms, a benzyl group, a tetrahydropyrannyl group, an RCRDRESi group, in which identical or different RC,RD and RE, independently from one another each represent an alkyl radical containing from 1 to 4 carbon atoms or a phenyl group. It particularly concerns the Si(Me)2Cme3 orxe2x80x94Si(PH)2CMe3 or SiMe3 groups.
As an example, the deprotection reactions of the compounds of formula (IIIa) or (IIIb), when Pxe2x80x2 is a tertbutyldiphenylsilyl group can be carried out by the action of ammonium tetrabutyl fluoride in solution in tetrahydrofuran.
When Pxe2x80x2 is a tetrahydropyrannyl group, the deprotection is carried out in the presence of an aqueous acid in an alcoholic solvent and preferably by the action of chlorohydric acid in methanol.
The action of a compound of formula R3xe2x80x94NHxe2x80x94R4 on the compounds of formula (IV) is carried out in standard conditions of nucleophile substitutions, notably in the presence of an aprotic solvent such as tetrahydrofuran, OPxe2x80x3 thus preferably represents an Oxe2x80x94SO2CH3, OSO2xe2x80x94PHxe2x80x94pMe, OSO2CPh3. OP can equally represent halogen (preferably bromine or iodine).
The alkylisation or acylsation reactions of the OH group in position 3 or 17 are carried out by standard methods known to the specialist.
The reduction of 17-ceto in a corresponding alcohol (R5=OH and R6=H) is carried out according to standard methods, notably by the action of an alkaline borohydrure such as sodium borohydrure in methanol or ethanol or by action of aluminium and lithium tetrahydrure.
The action of an organometallic on the 17-ceto makes it possible to have access to the products of formula (I) in which D represents the residue of a pentagonal ring as previously described, R5 is hydroxyl and R6 represents an alkyl, alkenyl, optionally substituted alkynyl radical.
The organometallic derived from an alkyl, alkenyl or alkynyl is chosen from amongst the magnesians of formula AlkMgHal and the lithiens of formula AlkLi in which Alk represents an alkyl, alkenyl or alkynyl group containing at the most 8 carbon atoms and Hal represents a halogen atom. In a preferred method of carrying out the process, Hal represents a chloride, bromine or iodine atom, preferably bromine.
The reaction preferably takes place in the presence of cerium chloride. In a preferred method of carrying out the process Hal represents a chloride, bromine or iodine atom, preferably bromine.
To obtain the compounds of formula (I) with R5 is a hydroxyl and R6 is a CF3 group, the reaction is carried out by action of CF3SiMe3 on the 17-ceto, followed by the action of a deprotection reagent such as ammonium tetrabutyl fluoride.
The lactonisation reaction starting with 17 ceto is carried out according to the STURTZ method (ref: G STURTZ and J-J. YAOUANC, synthesis, (1980), 289) notably in the presence of allyl bisdimethylamidophosphate in the presence of an alkyllithien such as N-butyllithium in tetrahydrofuran.
The reaction of total or partial reduction when R6 is an alkenyl or alkynyl radical or when R5 and R6 together with the carbon that carries them, form an Oxe2x80x94(CH2)1xe2x80x2xe2x80x94CHxe2x95x90CHxe2x80x94group, can be carried out either totally by the action of hydrogen in the presence of a catalyst such as palladium on carbon or a rhodium catalyst such as Wilkinson""s reagent or partially (alkynyl becomes alkenyl) by the action of a poisoned catalyst such as palladium on barium sulphate poisoned by pyridine or triethylamine.
The reactions of esterification and salification are carried out by standard methods known to the specialist.
The invention has more particularly as its aim a process for preparing compounds of formula (Ixe2x80x2) as previously described, in which a compound of general formula (IIxe2x80x2) is submitted: 
in which
K, Rxe2x80x25 and Rxe2x80x26 are as previously described, or in which Rxe2x80x25 is a CN radical and Rxe2x80x26 is a protected hydroxyl, successive to the following reactions:
a) action of a compound of formula (IIIxe2x80x2): 
xe2x80x83in which M and P are as previously described, then deprotection of one or several of the protected reactive functions, in order to obtain a compound of formula (IIIxe2x80x2a): 
b) action, optionally, of a halogenation reagent in order to obtain a compound of formula (IIIxe2x80x2b): 
xe2x80x83Halxe2x80x2 representing a chlorine or bromine atom,
c) activation of the OH function then action of an aromatisation reagent of ring (A) on the compounds of formula (IIIa) or (IIIb), then the action of a base to obtain the compounds of formula (IVxe2x80x2): 
xe2x80x83Xxe2x80x2 and Pxe2x80x3 are as previously described,
d) action of an amine of formula (Vxe2x80x2): 
xe2x80x83Rxe2x80x23 and Rxe2x80x24 as previously described in order to obtain certain components of formula (Ixe2x80x2), the compounds of formulas (IIIxe2x80x2a), (IIIxe2x80x2b), (IVxe2x80x2) and (Ixe2x80x2) submitted, if desired or if necessary to one or several of the following reactions:
protection/deprotection of the OH group(s),
alkylation/acylation of the OH group(s),
action of a reduction agent when Rxe2x80x25 and Rxe2x80x26 together form an oxo group,
action of an organometallic or CF3SiMe3 on the compounds of formula (IVxe2x80x2) or (Ixe2x80x2) with Rxe2x80x25 and Rxe2x80x26 together forming an oxo group,
action of a lactonisation agent on the compounds of formula (IVxe2x80x2) or (Ixe2x80x2) with Rxe2x80x25 and R6 together forming an oxo group,
action of a reduction agent of the double bond, when Rxe2x80x25 and Rxe2x80x26 together with the carbon that carries them, form an Oxe2x80x94(CH2)1xe2x80x2xe2x80x94CHxe2x95x90CHxe2x80x94group,
action of a reduction agent, when Rxe2x80x26 is an alkenyl or alkynyl radical containing from 2 to 6 carbon atoms,
salification.
The compounds of general formula (I) as well as their addition salts with pharmaceutically acceptable acids notably having oestrogen, anti-oestrogen and antiproliferative activities.
As such, the compounds of formula (I) can be used in the treatment of disorders linked to hypofolliculitis, for example amenorrhea, dysmenorrhea, repeated abortions, premenstrual disorders, in the treatment of certain oestrogen dependent pathologies such as prostatic adenomas or carcinomas, mammary carcinomas and its metastases or the treatment of benign breast tumours, as anti-uterotrophic as well as in the hormone replacement treatment of the menopause or perimenopause.
Amongst the symptoms and the consequences linked to the menopause, are more precisely meant the hot flushes, sweats, vaginal atrophia and dryness, urinary indications and in the long term lessening of bone mass and the increase of the risk of fracture, as well as the loss of the cardio-vascular protection offered by oestrogens.
In particular, the compounds of formula (I) as well as their addition salts with pharmaceutically acceptable acids or the bases can thus be used in the prevention or the treatment of osteoporosis.
The compounds of formula (I) as well as their addition salts with pharmaceutically acceptable acids or bases, can equally be used in the prevention or treatment of osteoporosis in men.
They can equally be used in the prevention or the (for example cortisone or connected with immobilisation) treatment of secondary osteoporosis.
The compounds of formula (I) as well as their addition salts with pharmaceutically acceptable acids or bases notably have a dissociated oestrogenic activity.
By dissociated oestrogenic activity, is meant oestrogenic activity at bone level whilst only manifesting a minimal activity at uterine level thus leading to the absence of endometrial proliferation (activity well below that of oestradiol).
Furthermore, the compounds according to the invention present the following advantages:
They show an anti-oestrogen and/or antiproliferative activity in the breast. Unlike oestradiol they do not stimulate the growth of human mammary tumour cells and can even inhibit their growth. The compounds according to the invention are thus particularly advantageous for the treatment of the menopause as far as women at risk from mammary cancer are concerned (prior family history) who are thus excluded from replacement oestradiol treatment.
They can equally be used in the treatment of mammary cancers.
They lead to a lowering in the level of serum cholesterol to an at least equivalent level of that induced by oestradiol. They thus reinforce cardiovascular protection.
Finally these compounds according to the invention do not show any oestrogen activity at uterine level, do not need to be administered in association with a progestomimetic compound.
The invention thus has as its object the compounds of formula (I) as well as their addition salts with pharmaceutically acceptable acids or bases, as medicines.
The invention has more particularly as its object the compounds of formula (I) as well as their addition salts with the pharmaceutically acceptable acids or bases, as medicines intended for the prevention or treatment of osteoporosis.
The invention extends to pharmaceutical compositions containing as active ingredient at least one of the medicines as described above.
The compounds of formula (I) are used by digestive, parenteral or local route, for example by percutaneous route. They can be prescribed in the form of simple tablets or sugar coated pills, capsules, granules, suppositories, pessaries, injectable preparations, ointments, creams, gels, microspheres, implants, intravaginal rings, patches, which are prepared according to usual methods.
The active ingredient(s) can be incorporated into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non aqueous mediums, fatty bodies of animal or vegetable origin, paraffin derivatives, glycols, various dilution, dispersant or emulsifying agents, preservatives.
The useful dosage varies according to the condition to be treated and the administration route; it can vary for example from 1 to 1000 mg per day in adults by oral route.
The compounds of general formula (II) or (IIxe2x80x2) are compounds known and described in the European Patent 0057115.
The compounds of formula (III) are known or are easily accessible to the specialist starting with the corresponding aromatic halides. The amines of formula (V) are equally known or easily accessible to a specialist.
The invention equally has as its aim, as intermediary products, the compounds of formula (IIIa), (IIIb), (IIIxe2x80x2a), (IIIb), (IV) or (IVxe2x80x2).